a Department of Laboratory Medicine , ShengJing Hospital of China Medical University , Shenyang , China.
b Department of Immunology , China Medical University , Shenyang , China.
Cancer Biol Ther. 2019;20(3):284-294. doi: 10.1080/15384047.2018.1529095. Epub 2018 Oct 25.
Ixazomib (Ninlaro), a novel proteasome inhibitor, has been developed for the treatment of many cancers and has demonstrated anti-tumor efficacy against various malignancies. However, the mechanism of the anti-tumor effect of ixazomib in colorectal cancer (CRC) cells remains unclear.
MTS and flow cytometry were performed to determine the effect of ixazomib on CRC cells. Western blotting and real-time RT-PCR were performed to detect ixazomib-induced DR5 upregulation. ChIP was performed to detect CHOP binding to DR5 promoter. Finally, xenograft experiments were carried out to measure the antitumor effect of ixazomib in vivo.
In this study, we revealed the mechanism by which ixazomib inhibits the growth of CRC cells. Our findings indicated that ixazomib treatment induces CHOP-dependent DR5 induction, irrespective of p53 status. Furthermore, DR5 is necessary for ixazomib-mediated apoptosis. Ixazomib also synergized with TRAIL to induce marked apoptosis via DR5 in CRC cells.
Our findings further suggested that ixazomib sensitizes TRAIL/death receptor signaling pathway-targeted CRC and suggested that DR5 induction could be a valuable indicator of ixazomib sensitivity.
伊沙佐米（Ninlaro），一种新型蛋白酶体抑制剂，已被开发用于治疗多种癌症，并已证明对各种恶性肿瘤具有抗肿瘤功效。然而，伊沙佐米在结直肠癌（CRC）细胞中的抗肿瘤作用机制尚不清楚。
采用 MTS 和流式细胞术检测伊沙佐米对 CRC 细胞的影响。采用 Western blot 和实时 RT-PCR 检测伊沙佐米诱导的 DR5 上调。采用 CHIP 检测 CHOP 与 DR5 启动子的结合。最后，进行异种移植实验以测量伊沙佐米在体内的抗肿瘤作用。
在这项研究中，我们揭示了伊沙佐米抑制 CRC 细胞生长的机制。我们的研究结果表明，伊沙佐米治疗诱导 CHOP 依赖性 DR5 诱导，与 p53 状态无关。此外，DR5 是伊沙佐米介导的细胞凋亡所必需的。伊沙佐米还与 TRAIL 协同作用，通过 CRC 细胞中的 DR5 诱导明显的凋亡。
我们的研究结果进一步表明，伊沙佐米使 TRAIL/死亡受体信号通路靶向的 CRC 敏感，并表明 DR5 诱导可能是伊沙佐米敏感性的一个有价值的指标。
